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  1. Article ; Online: T cells use distinct topographical and membrane receptor scanning strategies that individually coalesce during receptor recognition.

    Cai, En / Beppler, Casey / Eichorst, John / Marchuk, Kyle / Eastman, Scott W / Krummel, Matthew F

    Proceedings of the National Academy of Sciences of the United States of America

    2022  Volume 119, Issue 32, Page(s) e2203247119

    Abstract: During immune surveillance, CD8 T cells scan the surface of antigen-presenting cells using dynamic microvillar palpation and movements as well as by having their receptors preconcentrated into patches. Here, we use real-time lattice light-sheet ... ...

    Abstract During immune surveillance, CD8 T cells scan the surface of antigen-presenting cells using dynamic microvillar palpation and movements as well as by having their receptors preconcentrated into patches. Here, we use real-time lattice light-sheet microscopy to demonstrate the independence of microvillar and membrane receptor patch scanning. While T cell receptor (TCR) patches can distribute to microvilli, they do so stochastically and not preferentially as for other receptors such as CD62L. The distinctness of TCR patch movement from microvillar movement extends to many other receptors that form patches that also scan independent of the TCR. An exception to this is the CD8 coreceptor which largely comigrates in patches that overlap with or are closely adjacent to those containing TCRs. Microvilli that assemble into a synapse contain various arrays of the engaged patches, notably of TCRs and the inhibitory receptor PD-1, creating a pastiche of occupancies that vary from microvillar contact to contact. In summary, this work demonstrates that localization of receptor patches within the membrane and on microvillar projections is random prior to antigen detection and that such random variation may play into the generation of many individually composed receptor patch compositions at a single synapse.
    MeSH term(s) Antigen-Presenting Cells/cytology ; CD8-Positive T-Lymphocytes/cytology ; Cell Membrane/metabolism ; Humans ; Immunologic Surveillance ; Immunological Synapses ; Microvilli/metabolism ; Receptors, Antigen, T-Cell/metabolism
    Chemical Substances Receptors, Antigen, T-Cell
    Language English
    Publishing date 2022-08-01
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.2203247119
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  2. Article ; Online: Hyperstabilization of T cell microvilli contacts by chimeric antigen receptors.

    Beppler, Casey / Eichorst, John / Marchuk, Kyle / Cai, En / Castellanos, Carlos A / Sriram, Venkataraman / Roybal, Kole T / Krummel, Matthew F

    The Journal of cell biology

    2022  Volume 222, Issue 3

    Abstract: T cells typically recognize their ligands using a defined cell biology-the scanning of their membrane microvilli (MV) to palpate their environment-while that same membrane scaffolds T cell receptors (TCRs) that can signal upon ligand binding. Chimeric ... ...

    Abstract T cells typically recognize their ligands using a defined cell biology-the scanning of their membrane microvilli (MV) to palpate their environment-while that same membrane scaffolds T cell receptors (TCRs) that can signal upon ligand binding. Chimeric antigen receptors (CARs) present both a therapeutic promise and a tractable means to study the interplay between receptor affinity, MV dynamics and T cell function. CARs are often built using single-chain variable fragments (scFvs) with far greater affinity than that of natural TCRs. We used high-resolution lattice lightsheet (LLS) and total internal reflection fluorescence (TIRF) imaging to visualize MV scanning in the context of variations in CAR design. This demonstrated that conventional CARs hyper-stabilized microvillar contacts relative to TCRs. Reducing receptor affinity, antigen density, and/or multiplicity of receptor binding sites normalized microvillar dynamics and synapse resolution, and effector functions improved with reduced affinity and/or antigen density, highlighting the importance of understanding the underlying cell biology when designing receptors for optimal antigen engagement.
    MeSH term(s) Microvilli/metabolism ; Receptors, Antigen, T-Cell/metabolism ; Receptors, Chimeric Antigen/genetics ; Receptors, Chimeric Antigen/metabolism ; Single-Chain Antibodies/metabolism ; T-Lymphocytes ; Humans ; Antigens
    Chemical Substances Receptors, Antigen, T-Cell ; Receptors, Chimeric Antigen ; Single-Chain Antibodies ; Antigens
    Language English
    Publishing date 2022-12-15
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 218154-x
    ISSN 1540-8140 ; 0021-9525
    ISSN (online) 1540-8140
    ISSN 0021-9525
    DOI 10.1083/jcb.202205118
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  3. Article ; Online: Enhanced identification of synergistic and antagonistic emergent interactions among three or more drugs.

    Tekin, Elif / Beppler, Casey / White, Cynthia / Mao, Zhiyuan / Savage, Van M / Yeh, Pamela J

    Journal of the Royal Society, Interface

    2016  Volume 13, Issue 119

    Abstract: Interactions among drugs play a critical role in the killing efficacy of multi-drug treatments. Recent advances in theory and experiment for three-drug interactions enable the search for emergent interactions-ones not predictable from pairwise ... ...

    Abstract Interactions among drugs play a critical role in the killing efficacy of multi-drug treatments. Recent advances in theory and experiment for three-drug interactions enable the search for emergent interactions-ones not predictable from pairwise interactions. Previous work has shown it is easier to detect synergies and antagonisms among pairwise interactions when a rescaling method is applied to the interaction metric. However, no study has carefully examined whether new types of normalization might be needed for emergence. Here, we propose several rescaling methods for enhancing the classification of the higher order drug interactions based on our conceptual framework. To choose the rescaling that best separates synergism, antagonism and additivity, we conducted bacterial growth experiments in the presence of single, pairwise and triple-drug combinations among 14 antibiotics. We found one of our rescaling methods is far better at distinguishing synergistic and antagonistic emergent interactions than any of the other methods. Using our new method, we find around 50% of emergent interactions are additive, much less than previous reports of greater than 90% additivity. We conclude that higher order emergent interactions are much more common than previously believed, and we argue these findings for drugs suggest that appropriate rescaling is crucial to infer higher order interactions.
    MeSH term(s) Anti-Bacterial Agents/pharmacology ; Drug Antagonism ; Drug Evaluation, Preclinical ; Drug Synergism ; Escherichia coli/growth & development
    Chemical Substances Anti-Bacterial Agents
    Language English
    Publishing date 2016-06-08
    Publishing country England
    Document type Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, Non-U.S. Gov't
    ZDB-ID 2156283-0
    ISSN 1742-5662 ; 1742-5689
    ISSN (online) 1742-5662
    ISSN 1742-5689
    DOI 10.1098/rsif.2016.0332
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  4. Article ; Online: Visualizing Synaptic Transfer of Tumor Antigens among Dendritic Cells.

    Ruhland, Megan K / Roberts, Edward W / Cai, En / Mujal, Adriana M / Marchuk, Kyle / Beppler, Casey / Nam, David / Serwas, Nina K / Binnewies, Mikhail / Krummel, Matthew F

    Cancer cell

    2020  Volume 37, Issue 6, Page(s) 786–799.e5

    Abstract: Generation of tumor-infiltrating lymphocytes begins when tumor antigens reach the lymph node (LN) to stimulate T cells, yet we know little of how tumor material is disseminated among the large variety of antigen-presenting dendritic cell (DC) subsets in ... ...

    Abstract Generation of tumor-infiltrating lymphocytes begins when tumor antigens reach the lymph node (LN) to stimulate T cells, yet we know little of how tumor material is disseminated among the large variety of antigen-presenting dendritic cell (DC) subsets in the LN. Here, we demonstrate that tumor proteins are carried to the LN within discrete vesicles inside DCs and are then transferred among DC subsets. A synapse is formed between interacting DCs and vesicle transfer takes place in the absence of free exosomes. DCs -containing vesicles can uniquely activate T cells, whereas DCs lacking them do not. Understanding this restricted sharing of tumor identity provides substantial room for engineering better anti-tumor immunity.
    MeSH term(s) Animals ; Antigen Presentation/immunology ; Antigens, Neoplasm/immunology ; Dendritic Cells/cytology ; Dendritic Cells/immunology ; Dendritic Cells/metabolism ; Male ; Melanoma, Experimental/immunology ; Melanoma, Experimental/metabolism ; Melanoma, Experimental/pathology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Myeloid Cells/cytology ; Myeloid Cells/immunology ; Myeloid Cells/metabolism ; Receptors, CCR2/physiology ; Receptors, CCR7/physiology ; Synapses/immunology ; Synapses/metabolism ; Synapses/pathology ; T-Lymphocytes/cytology ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism
    Chemical Substances Antigens, Neoplasm ; Ccr2 protein, mouse ; Ccr7 protein, mouse ; Receptors, CCR2 ; Receptors, CCR7
    Language English
    Publishing date 2020-06-18
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2078448-X
    ISSN 1878-3686 ; 1535-6108
    ISSN (online) 1878-3686
    ISSN 1535-6108
    DOI 10.1016/j.ccell.2020.05.002
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 5650: Show issues Location:
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  5. Article ; Online: When more is less: Emergent suppressive interactions in three-drug combinations.

    Beppler, Casey / Tekin, Elif / White, Cynthia / Mao, Zhiyuan / Miller, Jeffrey H / Damoiseaux, Robert / Savage, Van M / Yeh, Pamela J

    BMC microbiology

    2017  Volume 17, Issue 1, Page(s) 107

    Abstract: Background: In drug-drug interactions, there are surprising cases in which the growth inhibition ... in this study. Most cases of suppression we find (97%) are "hidden" cases for which the triple-drug bacterial ...

    Abstract Background: In drug-drug interactions, there are surprising cases in which the growth inhibition of bacteria by a single antibiotic decreases when a second antibiotic is added. These interactions are termed suppressive and have been argued to have the potential to limit the evolution of resistance. Nevertheless, little attention has been given to suppressive interactions because clinical studies typically search for increases in killing efficiency and because suppressive interactions are believed to be rare based on pairwise studies.
    Results: Here, we quantify the effects of single-, double-, and triple-drug combinations from a set of 14 antibiotics and 3 bacteria strains, totaling 364 unique three-drug combinations per bacteria strain. We find that increasing the number of drugs can increase the prevalence of suppressive interactions: 17% of three-drug combinations are suppressive compared to 5% of two-drug combinations in this study. Most cases of suppression we find (97%) are "hidden" cases for which the triple-drug bacterial growth is less than the single-drug treatments but exceeds that of a pairwise combination.
    Conclusions: We find a surprising number of suppressive interactions in higher-order drug combinations. Without examining lower-order (pairwise) bacterial growth, emergent suppressive effects would be missed, potentially affecting our understanding of evolution of resistance and treatment strategies for resistant pathogens. These findings suggest that careful examination of the full factorial of drug combinations is needed to uncover suppressive interactions in higher-order combinations.
    Language English
    Publishing date 2017-05-06
    Publishing country England
    Document type Journal Article
    ISSN 1471-2180
    ISSN (online) 1471-2180
    DOI 10.1186/s12866-017-1017-3
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  6. Article ; Online: Deoxycytidine deaminase-deficient Escherichia coli strains display acute sensitivity to cytidine, adenosine, and guanosine and increased sensitivity to a range of antibiotics, including vancomycin.

    Kang, Tina Manzhu / Yuan, Jessica / Zhou, Alice / Beppler, Casey / Miller, Jeffrey H

    Journal of bacteriology

    2014  Volume 196, Issue 11, Page(s) 1950–1957

    Abstract: We show here that deoxycytidine deaminase (DCD)-deficient mutants of Escherichia coli are hypersensitive to killing by exogenous cytidine, adenosine, or guanosine, whereas wild-type cells are not. This hypersensitivity is reversed by exogenous thymidine. ...

    Abstract We show here that deoxycytidine deaminase (DCD)-deficient mutants of Escherichia coli are hypersensitive to killing by exogenous cytidine, adenosine, or guanosine, whereas wild-type cells are not. This hypersensitivity is reversed by exogenous thymidine. The mechanism likely involves the allosteric regulation of ribonucleotide reductase and severe limitations of the dTTP pools, resulting in thymineless death, the phenomenon of cell death due to thymidine starvation. We also report here that DCD-deficient mutants of E. coli are more sensitive to a series of different antibiotics, including vancomycin, and we show synergistic killing with the combination of vancomycin and cytidine. One possibility is that a very low, subinhibitory concentration of vancomycin enters Gram-negative cells and that this concentration is potentiated by chromosomal lesions resulting from the thymineless state. A second possibility is that the metabolic imbalance resulting from DCD deficiency affects the assembly of the outer membrane, which normally presents a barrier to drugs such as vancomycin. We consider these findings with regard to ideas of rendering Gram-negative bacteria sensitive to drugs such as vancomycin.
    MeSH term(s) Adenosine/pharmacology ; Anti-Bacterial Agents/pharmacology ; Cytidine/pharmacology ; Cytidine Deaminase ; Drug Resistance, Bacterial ; Escherichia coli/drug effects ; Escherichia coli/enzymology ; Gene Deletion ; Gene Expression Regulation, Bacterial/physiology ; Gene Expression Regulation, Enzymologic/physiology ; Guanosine/pharmacology ; Nucleoside Deaminases/genetics ; Nucleoside Deaminases/metabolism ; Vancomycin/pharmacology
    Chemical Substances Anti-Bacterial Agents ; Guanosine (12133JR80S) ; Cytidine (5CSZ8459RP) ; Vancomycin (6Q205EH1VU) ; Nucleoside Deaminases (EC 3.5.4.-) ; Cytidine Deaminase (EC 3.5.4.5) ; deoxycytidine deaminase (EC 3.5.4.5) ; Adenosine (K72T3FS567)
    Language English
    Publishing date 2014-03-14
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2968-3
    ISSN 1098-5530 ; 0021-9193
    ISSN (online) 1098-5530
    ISSN 0021-9193
    DOI 10.1128/JB.01383-13
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  7. Article ; Online: Synergistic interactions of vancomycin with different antibiotics against Escherichia coli: trimethoprim and nitrofurantoin display strong synergies with vancomycin against wild-type E. coli.

    Zhou, Alice / Kang, Tina Manzhu / Yuan, Jessica / Beppler, Casey / Nguyen, Caroline / Mao, Zhiyuan / Nguyen, Minh Quan / Yeh, Pamela / Miller, Jeffrey H

    Antimicrobial agents and chemotherapy

    2015  Volume 59, Issue 1, Page(s) 276–281

    Abstract: Gram-negative bacteria are normally resistant to the antibiotic vancomycin (VAN), which cannot significantly penetrate the outer membrane. We used Escherichia coli mutants that are partially sensitive to VAN to study synergies between VAN and 10 other ... ...

    Abstract Gram-negative bacteria are normally resistant to the antibiotic vancomycin (VAN), which cannot significantly penetrate the outer membrane. We used Escherichia coli mutants that are partially sensitive to VAN to study synergies between VAN and 10 other antibiotics representing six different functional categories. We detected strong synergies with VAN and nitrofurantoin (NTR) and with VAN and trimethoprim (TMP) and moderate synergies with other drugs, such as aminoglycosides. These synergies are powerful enough to show the activity of VAN against wild-type E. coli at concentrations of VAN as low as 6.25 μg/ml. This suggests that a very small percentage of exogenous VAN does enter E. coli but normally has insignificant effects on growth inhibition or cell killing. We used the results of pairwise interactions with VAN and the other 10 antibiotics tested to place VAN into a functional category of its own, as previously defined by Yeh et al. (P. Yeh, A. I. Tschumi, and R. Kishony, Nat Genet 28:489-494, 2006, http://dx.doi.org/10.1038/ng1755).
    MeSH term(s) Anti-Bacterial Agents/pharmacology ; Carrier Proteins/genetics ; Dose-Response Relationship, Drug ; Drug Synergism ; Drug Therapy, Combination ; Escherichia coli/drug effects ; Escherichia coli/genetics ; Escherichia coli Proteins/genetics ; Mutation ; Nitrofurantoin/pharmacology ; Peptidylprolyl Isomerase/genetics ; Trimethoprim/pharmacology ; Vancomycin/pharmacology
    Chemical Substances Anti-Bacterial Agents ; Carrier Proteins ; Escherichia coli Proteins ; Vancomycin (6Q205EH1VU) ; Nitrofurantoin (927AH8112L) ; Trimethoprim (AN164J8Y0X) ; SurA protein, E coli (EC 5.2.1.-) ; Peptidylprolyl Isomerase (EC 5.2.1.8)
    Language English
    Publishing date 2015-01
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 217602-6
    ISSN 1098-6596 ; 0066-4804
    ISSN (online) 1098-6596
    ISSN 0066-4804
    DOI 10.1128/AAC.03502-14
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Visualizing dynamic microvillar search and stabilization during ligand detection by T cells.

    Cai, En / Marchuk, Kyle / Beemiller, Peter / Beppler, Casey / Rubashkin, Matthew G / Weaver, Valerie M / Gérard, Audrey / Liu, Tsung-Li / Chen, Bi-Chang / Betzig, Eric / Bartumeus, Frederic / Krummel, Matthew F

    Science (New York, N.Y.)

    2017  Volume 356, Issue 6338

    Abstract: During immune surveillance, T cells survey the surface of antigen-presenting cells. In searching for peptide-loaded major histocompatibility complexes (pMHCs), they must solve a classic trade-off between speed and sensitivity. It has long been supposed ... ...

    Abstract During immune surveillance, T cells survey the surface of antigen-presenting cells. In searching for peptide-loaded major histocompatibility complexes (pMHCs), they must solve a classic trade-off between speed and sensitivity. It has long been supposed that microvilli on T cells act as sensory organs to enable search, but their strategy has been unknown. We used lattice light-sheet and quantum dot-enabled synaptic contact mapping microscopy to show that anomalous diffusion and fractal organization of microvilli survey the majority of opposing surfaces within 1 minute. Individual dwell times were long enough to discriminate pMHC half-lives and T cell receptor (TCR) accumulation selectively stabilized microvilli. Stabilization was independent of tyrosine kinase signaling and the actin cytoskeleton, suggesting selection for avid TCR microclusters. This work defines the efficient cellular search process against which ligand detection takes place.
    MeSH term(s) Actin Cytoskeleton/metabolism ; Animals ; Antigens/immunology ; Fractals ; Ligands ; Mice ; Microscopy/methods ; Microvilli/chemistry ; Microvilli/metabolism ; Quantum Dots ; Receptors, Antigen, T-Cell/metabolism ; T-Lymphocytes/cytology ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism
    Chemical Substances Antigens ; Ligands ; Receptors, Antigen, T-Cell
    Language English
    Publishing date 2017-05-11
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 128410-1
    ISSN 1095-9203 ; 0036-8075
    ISSN (online) 1095-9203
    ISSN 0036-8075
    DOI 10.1126/science.aal3118
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  9. Article: Deoxycytidine Deaminase-Deficient Escherichia coli Strains Display Acute Sensitivity to Cytidine, Adenosine, and Guanosine and Increased Sensitivity to a Range of Antibiotics, Including Vancomycin

    Kang, Tina Manzhu / Yuan, Jessica / Zhou, Alice / Beppler, Casey / Miller, Jeffrey H

    Journal of bacteriology. 2014 June 1, v. 196, no. 11

    2014  

    Abstract: We show here that deoxycytidine deaminase (DCD)-deficient mutants of Escherichia coli are hypersensitive to killing by exogenous cytidine, adenosine, or guanosine, whereas wild-type cells are not. This hypersensitivity is reversed by exogenous thymidine. ...

    Abstract We show here that deoxycytidine deaminase (DCD)-deficient mutants of Escherichia coli are hypersensitive to killing by exogenous cytidine, adenosine, or guanosine, whereas wild-type cells are not. This hypersensitivity is reversed by exogenous thymidine. The mechanism likely involves the allosteric regulation of ribonucleotide reductase and severe limitations of the dTTP pools, resulting in thymineless death, the phenomenon of cell death due to thymidine starvation. We also report here that DCD-deficient mutants of E. coli are more sensitive to a series of different antibiotics, including vancomycin, and we show synergistic killing with the combination of vancomycin and cytidine. One possibility is that a very low, subinhibitory concentration of vancomycin enters Gram-negative cells and that this concentration is potentiated by chromosomal lesions resulting from the thymineless state. A second possibility is that the metabolic imbalance resulting from DCD deficiency affects the assembly of the outer membrane, which normally presents a barrier to drugs such as vancomycin. We consider these findings with regard to ideas of rendering Gram-negative bacteria sensitive to drugs such as vancomycin.
    Keywords Escherichia coli ; Gram-negative bacteria ; adenosine ; bacteriology ; cell death ; cytidine ; cytidine deaminase ; drugs ; guanosine ; hypersensitivity ; mutants ; ribonucleotide reductase ; thymidine ; vancomycin
    Language English
    Dates of publication 2014-0601
    Size p. 1950-1957.
    Publishing place American Society for Microbiology
    Document type Article
    ZDB-ID 2968-3
    ISSN 1098-5530 ; 0021-9193
    ISSN (online) 1098-5530
    ISSN 0021-9193
    DOI 10.1128/JB.01383-13
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  10. Article ; Online: Uncovering emergent interactions in three-way combinations of stressors.

    Beppler, Casey / Tekin, Elif / Mao, Zhiyuan / White, Cynthia / McDiarmid, Cassandra / Vargas, Emily / Miller, Jeffrey H / Savage, Van M / Yeh, Pamela J

    Journal of the Royal Society, Interface

    2016  Volume 13, Issue 125

    Abstract: Understanding how multiple stressors interact is needed to predict the dynamical outcomes of diverse biological systems, ranging from drug-resistant pathogens that are combated and treated with combination drug therapies to ecosystems impacted by ... ...

    Abstract Understanding how multiple stressors interact is needed to predict the dynamical outcomes of diverse biological systems, ranging from drug-resistant pathogens that are combated and treated with combination drug therapies to ecosystems impacted by environmental toxicants or disturbances. Nevertheless, extensive studies of higher-order (more than two component) interactions have been lacking. Here, we conduct experiments using 20 three-drug combinations and their effects on the bacterial growth of Escherichia coli We report our measurements of growth rates in single, pairwise and triple-drug combinations. To uncover emergent interactions, we derive a simple framework to calculate expectations for three-way interactions based on the measured impact of each individual stressor and of each pairwise interaction. Using our framework, we find that (i) emergent antagonisms are more common than emergent synergies and (ii) emergent antagonisms are more common and emergent synergies are more rare than would be inferred from measures of net effects that do not disentangle pairwise interactions from three-way interactions.
    MeSH term(s) Anti-Bacterial Agents/pharmacology ; Escherichia coli/growth & development ; Models, Biological ; Stress, Physiological/drug effects
    Chemical Substances Anti-Bacterial Agents
    Language English
    Publishing date 2016-12-13
    Publishing country England
    Document type Journal Article
    ZDB-ID 2156283-0
    ISSN 1742-5662 ; 1742-5689
    ISSN (online) 1742-5662
    ISSN 1742-5689
    DOI 10.1098/rsif.2016.0800
    Database MEDical Literature Analysis and Retrieval System OnLINE

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